Chronic Pulmonary Hypertension March 3, 2009 Henry Green, MD, FACC, FACP Acute pulmonary hypertension Acute pulmonary hypertension occurs in settings such as pulmonary embolism and adult respiratory distress syndrome. It is not the topic of this essay. Chronic pulmonary hypertension Pulmonary arterial hypertension is the result of humoral and structural changes in the pulmonary vasculature. Pulmonary venous hypertension is caused by disease of the left heart. Classification of chronic pulmonary hypertension1,3 Based on the 2003 World Symposium on Pulmonary Hypertension Group 1: Pulmonary arterial hypertension involving the small pulmonary arteries Idiopathic Familial (autosomal dominant) Associated with: Collagen vascular disease (commonly scleroderma) Congenital systemic-to-pulmonary shunts Portal hypertension Human immunodeficiency virus infection Drugs and toxins (fenfluramine, stimulants, cocaine) Other (thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies including sickle cell disease, myeloproliferative disorders, splenectomy) Associated with significant venous or capillary involvement Pulmonary veno-occlusive disease Pulmonary capillary hemangiomatosis Persistent pulmonary hypertension of the newborn Group 2: Pulmonary hypertension with left heart disease (pulmonary venous hypertension) Left-sided atrial or ventricular heart disease Left-sided valvular heart disease Group 3: Pulmonary hypertension associated with lung diseases or hypoxemia Chronic obstructive pulmonary disease Interstitial lung disease Sleep-disordered breathing Alveolar hypoventilation disorders Chronic exposure to high altitude Developmental abnormalities Group 4: Pulmonary hypertension due to chronic thrombotic or embolic disease Thromboembolic obstruction of proximal pulmonary arteries Thromboembolic obstruction of distal pulmonary arteries Nonthrombotic pulmonary embolism (tumor, parasites, foreign material) Group 5: Miscellaneous Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

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Pulmonary arterial hypertension (PAH) Pulmonary arterial hypertension is defined as sustained elevation of pulmonary arterial pressure to over 25 mm at rest or 30 mm with exercise. The mean pulmonary capillary wedge pressure is less than 15 mm It is a progressive disease characterized by elevated pulmonary arterial pressure. It causes vascular injury and ultimately leads to right ventricular failure. Pathogenesis4 Several vasoactive substances have a role in the development of PAH: Prostacyclin is a vasodilator, inhibits platelet activation, and is antiproliferative. Thromboxane A2 is a vasoconstrictor and platelet agonist. In pulmonary arterial hypertension, there an excess of thromboxane A2 and decreased production of prostacyclin. Endothelin-1, another vasoconstrictor, also promotes growth of pulmonary artery smooth muscle cells. Nitric oxide is a vasodilator and inhibits platelet activation and vascular smooth muscle proliferation. Its production is inhibited. Serotonin is a vasoconstrictor and promotes smooth muscle cell hypertrophy and hyperplasia. Its release from platelets increased in patients that take the appetite suppressant dexfenfluramine. Some other factors that have been implicated include vasoactive intestinal peptide and vascular endothelial growth factor. In addition to humoral factors, structural changes occur. There is endothelial proliferation, medial hypertrophy and intimal fibrosis. Plexiform lesions may occur in some forms of pulmonary arterial hypertension. Risk factors Diet drugs, namely fenfluramine and dexfenfluramine increase the risk of pulmonary arterial hypertension. This may occur in as little as 3-4 weeks, but the risk increases with longer use. Amphetamine and cocaine also confer increased risk of pulmonary hypertension. The reason for this is unknown. Associated diseases Scleroderma, especially the CREST syndrome can cause pulmonary arterial hypertension. Systemic lupus, mixed connective tissue disease, and rheumatoid arthritis also have been associated with the condition. Patients with human immunodeficiency virus may acquire pulmonary arterial hypertension, particularly when the disease is of long duration. 2

Human herpes virus may be associated with pulmonary arterial hypertension. Portal hypertension uncommonly leads to pulmonary arterial hypertension, usually a few years after the onset. Thrombocytosis sometimes causes pulmonary arterial hypertension, possibly by one or more of a number of factors. These include megakaryocyte plugging of the pulmonary arterioles, serotonin release, and other factors. Hemoglobinopathies (thalassemia and sickle cell disease) may be associated with pulmonary arterial hypertension. Patients with hereditary hemorrhagic telangiectasia may develop pulmonary arterial hypertension that is clinically identical with the idiopathic variety. Recognition Clinical findings Primary pulmonary hypertension is commoner in women. It can occur at any age, but is most commonly recognized between the ages of 36 to 50. Progressive dyspnea develops over months to years. As the disease progresses, exertional chest pain, syncope and dependent edema develop. Symptom severity is graded as follows: Class I No limitation of usual activity Class II Slight limitation of usual activity Class III Marked limitation of usual activity Class IV Inability to perform any activity without symptoms and/or signs of right heart failure A loud pulmonic second sound, a right ventricular heave, jugular venous distention, rightsided gallop sounds, and the murmur of tricuspid regurgitation are helpful signs. Peripheral edema and ascites may develop. Because of the broad differential diagnosis of these findings, the disease is often misdiagnosed. Familial cases of pulmonary arterial hypertension have been identified, tending to occur earlier in successive generations. Genetic testing and counseling may be advisable. Screening is also recommended for patients with scleroderma, portal hypertension, and other predisposing conditions. The workup should include pulmonary function testing, screening for connective tissue and liver disease, echocardiography, cardiac catheterization, and investigation for thromboembolic disease. A sleep study with oxygen monitoring is indicated. A very logical approach to the differential diagnosis is given in reference 5.

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Chest x-ray The pulmonary trunk and hilar vessels are enlarged, and there is “pruning” of the peripheral pulmonary vessels. In the lateral view, one sees the enlarged right ventricle encroaching on the retrosternal space. Computed tomography CT scan of the chest may help exclude some similar disorders, such as chronic thromboembolic disease and pulmonary veno-occlusive disease. Electrocardiogram The ECG typically shows right ventricular hypertrophy, right atrial enlargement and right axis deviation. Echocardiogram The echocardiogram can demonstrate right ventricular hypertrophy, tricuspid regurgitation and paradoxical septal motion. It permits estimation of pulmonary arterial pressure. There may be a pericardial effusion. It also detects many of the underlying causes of pulmonary hypertension, such as left heart disease. Combined with contrast, it can detect intracardiac shunting. Echocardiography is often the first clue to the presence of pulmonary arterial hypertension, but is not enough to make a definitive diagnosis. Pulmonary function testing Lung volumes may be normal or mildly restricted in pulmonary arterial hypertension. Carbon monoxide diffusing capacity is usually reduced. The primary use of pulmonary function testing here is to detect airway and pulmonary parenchymal disease. Lung scan Ventilation/perfusion scans are used to diagnose pulmonary thromboembolic disease. They are more reliable than CT scanning for detection of chronic clots. If abnormal, pulmonary arteriography should be done to confirm the diagnosis. Oximetry Exercise oximetry may reveal hypoxia, in which case oxygen should be prescribed. Overnight oximetry is useful for several reasons. It may disclose the presence of sleep apnea, which would contribute significantly to pulmonary hypertension. Even patients without sleep apnea frequently exhibit nocturnal desaturation. Lung biopsy Lung biopsy may identify a specific cause of secondary pulmonary hypertension, but carries significant risk in these patients. Right heart catheterization Right heart catheterization permits measurement of pulmonary arterial pressure and pulmonary vascular resistance. It assists in the differential diagnosis and in prognostication. An elevated wedge pressure indicates left heart disease. Intracardiac shunts are detected by measuring oxygen content of blood from the right heart chambers.

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The shunt flow can be quantitated by combining this information with the cardiac output. Very importantly, the response of pulmonary artery pressure to vasodilator agents is determined. A positive response requires that the pulmonary arterial pressure decrease by at least 10 mm to a level of 40 mm or less, with no change or an increase in cardiac output. Precautions Exercise Patients with PAH may engage in carefully graded physical activity, but not strenuous exercise because of the risk of syncope. Hot baths and showers can cause hypotension and should also be avoided. Diet Dietary sodium should be restricted. Patients should achieve an ideal body weight. Hypoxia Hypoxia induces systemic vasodilatation, but the pulmonary vessels undergo vasoconstriction. In acute situations, this is reversible, but chronic hypoxia causes structural remodeling. It is not a major factor in the etiology of pulmonary arterial hypertension, but may accelerate existing disease. Rubin5 advises patients not to go to altitudes above 1800 feet. Therefore, air travel is a risk. Oxygen supplementation should be used in this situation, and patients using oxygen at sea level may require higher flow rates (e.g. 3-4 l/min). Respiratory infections are also hazardous, and immunization against influenza and pneumonia should be given. Pregnancy Pregnancy constitutes a particular risk for these patients. The mortality is 30-50%, and most authorities recommend early abortion. Estrogen-containing contraceptives increase the risk of thromboembolism and are contraindicated. Contraindicated medications PAH patients should avoid decongestant drugs and herbal medications. In addition, bosentan interacts with certain other drugs, and this must be taken into account. Surgery Surgery carries further risks. It should be done by a team experienced in dealing with this disease. Vagally-induced bradycardia and vasodilatation can cause hypotension. Sedation can lead to hypoxia. Hypercarbia can result from insufflations of carbon dioxide during a laparoscopic procedure. Drug treatment There is no cure for pulmonary arterial hypertension. Consultation with a pulmonary hypertension specialist should always be obtained. A number of drugs have been found helpful. The choice must be made carefully and skillfully. The selection of a drug is usually done by hemodynamics testing. Combination therapy also appears to be promising.

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Epoprostenol, a prostacyclin analog, is considered the best treatment for patients in functional class IV. It must be given through a continuous infusion pump and an indwelling central venous catheter. A related drug, treprostinil, is effective subcutaneously or intravenously. Iloprost, another prostanoid, can be delivered by inhalation, but requires 6-9 doses per day. While effective, all of these products commonly produce side effects. Oral agents are usually used for patients in functional class II and III. Calcium channel blockers are useful in fewer than 10% of patients. In others, they may even be harmful (right ventricular failure, death). They should only be used in patients that have been shown to have a positive vasodilator response during right heart catheterization. It is often necessary to titrate to large doses. Patients must be followed closely, since the benefit is not sustained in half of them. The endothelin receptor antagonists (bosentan and ambrisentan) are oral agents that improve survival. Monthly liver function tests must be done. Sildenafil, a phosphodiesterase inhibitor, improves symptoms, hemodynamics and functional capacity. Adjunctive therapy Anticoagulation with warfarin improves survival in patients with idiopathic pulmonary hypertension and probably in portopulmonary hypertension and congenital heart disease. It is certainly indicated in patients with chronic thrombembolic pulmonary hypertension. Rubin5 cautions that there is increased risk of bleeding in patients with scleroderma, and of hemoptysis in those with congenital heart disease. He recommends deciding on a case by case basis in these patients. Digoxin has been used, but its benefit is not established, except for treatment of associated supraventricular arrhythmias. Diuretics are often required for dyspnea and right heart failure. Caution should be used to avoid hypotension and renal failure. Supplemental oxygen is recommended to maintain saturation above 90%. Acute exacerbations Some patients develop acute volume overload, hypotension and sometimes renal failure. Fluid challenges may actually exacerbate hypotension and reduce cardiac output. This may be due to septal shift due to right ventricular overload. In contrast, atrial septostomy can result in improvement. Complications, such as pulmonary embolism or infection should be identified and treated. Fluid overload may require diuresis. At times, it is necessary to use inotropes or pressors, mainly dobutamine, dopamine or norepinephrine. These are preferred over vasopressin, phenylephrine or milrinone.

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Surgical approaches Surgical approaches offer some hope for patients who do not respond to medical therapy. Atrial septostomy is used for palliation or as a bridge to surgery. By creating a right to left shunt, the right heart is decompressed. Lung transplantation is used when medical therapy fails. It is usually bilateral, and the 1year survival is 66-75%. Rarely, heart-lung transplantation is done. Prognosis There is much individual variation. Improved exercise performance may occur within weeks of starting drug therapy and often lasts for years. The prognosis is worse if right ventricular failure is present, or the cardiac index or mixed venous oxygen saturation are low. Other unfavorable indications include continued evidence of class III or IV symptoms, poor exercise capacity or elevated BNP level. These patients require close monitoring. One of the most useful tests is the 6-minute walk. Patients who cannot walk 300 m have a poor outlook. Other methods include right heart catheterization, echocardiography, and measurement of BNP level. Chronic cor pulmonale Chronic cor pulmonale is caused by chronic lung disease, either obstructive or restrictive. The effect of iloprost and other drugs for pulmonary hypertension has not been fully elucidated in these patients. Causes Chronic obstructive lung disease Interstitial fibrosis Connective tissue disease Chronic thromboembolic disease Tumor emboli Pulmonary hypertension due to chronic thrombotic or embolic disease Etiology This is the result of failure of pulmonary embolism to resolve. Treatment Proximal thromboembolic disease is treated surgically, using cardiopulmonary bypass and hypothermia. It is a fairly high-risk operation, with a mortality of 4-5% in the best of hands. However, survivors can expect a significant improvement in quality of life. An inferior vena cava filter is deployed, and permanent anticoagulation is required. Distal thromboembolic disease is treated medically. The drugs for pulmonary hypertension are modestly helpful.

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Pulmonary venous hypertension Pulmonary venous hypertension produces pulmonary congestion and edema. A pulmonary capillary wedge pressure over 15 mm is the defining characteristic. Causes Left ventricular failure Mitral valve disease Fibrosing mediastinitis Pulmonary venoocclusive disease Treatment The treatment is that of the underlying disease. Therapy directed at the pulmonary pressure may worsen pulmonary vascular congestion. However there is some support for the use of sildenafil. References 1. Minai OA and Budeve MM. Diagnostic strategies for suspected pulmonary arterial hypertension: a primer for the internist. Cleve Clin J Med 2007; 74:737-747 2. Minai OA and Budeve MM. Treating pulmonary arterial hypertension: Cautious hope in a deadly disease. Cleve Clin J Med 2007; 74:789-806 3. Chin KM and Rubin LJ. Pulmonary arterial hypertension. J Am Coll Cardiol 2008; 51:1527-1538 4. Farber HW and Loscalzo J. Mechanisms of disease: pulmonary arterial hypertension. New Engl J Med 2004; 351:1655-1665 5. Rubin LJ and Badesch DB. Evaluation and management of the patient with pulmonary arterial hypertension. Ann Intern Med 2005; 143:282-292

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